Fictional musician Dewey Cox begins his quest for stardom from humble beginnings in Springberry, Alabama in 1946. While playing with his brother Nate in a sequence of needlessly careless and dangerous acts, talking about the things he plans to do in his long life, Dewey accidentally cuts his brother in half at the waist with a machete. This leads Dewey’s father to frequently repeat the phrase “The wrong kid died.” It is this traumatic event that motivates Dewey to rise to stardom and “be double great for the both of us” as Nate made him promise. The trauma also causes Dewey to lose his sense of smell. After his brother’s death is announced by a physician making a housecall, Dewey’s mother sends him to the local store to buy a candle. There, he meets a blues guitarist (David “Honeyboy” Edwards), who lets Dewey play his guitar. Dewey is a natural.

After a successful, yet oddly controversial, talent show performance, then fourteen-year-old Dewey (now played by John C. Reilly) decides to leave Springberry with his newly-identified twelve-year-old girlfriend Edith (Kristen Wiig). They soon marry and have a baby. Edith begins to criticize Dewey and insist that his dream of being a musician will never happen. Dewey preaches to his wife that life is never easy; it’s a long hard walk, but he will walk hard. While working at an all-African American nightclub, Dewey gets a break when he replaces singer Bobby Shad (Craig Robinson) at the last minute, much to the delight of the Hasidic Jewish executives at the show.